Optimal Strategy of Switching from Clopidogrel to Ticagrelor in Chinese Acute Coronary Syndrome Patients with Complicated Coronary Artery Disease: The Switching from Clopidogrel to Ticagrelor (SHIFT-CACS) Study
Introduction
Dual antiplatelet therapy is a cornerstone in the management of acute coronary syndrome (ACS), particularly in patients with complicated coronary artery disease (CAD) undergoing percutaneous coronary intervention (PCI). Complicated CAD is associated with poor prognosis, necessitating more potent platelet inhibition. Ticagrelor, a member of the cyclopentyl-triazolo-pyrimidine class of P2Y12 blockers, offers faster, greater, and more consistent P2Y12 inhibition compared to clopidogrel. Ticagrelor has been shown to reduce ischemic events more effectively than clopidogrel, especially in patients with complicated CAD. However, ticagrelor is also associated with increased bleeding complications and dyspnea compared to clopidogrel. In clinical practice, many patients are initially treated with clopidogrel before coronary angiography, leading to a common need for switching from clopidogrel to ticagrelor. The optimal timing and dosage for this switch remain controversial, particularly in Chinese patients with ACS and complicated CAD. This study aimed to explore the optimal dose and time point for switching from clopidogrel to ticagrelor to balance increased platelet inhibition and reduced adverse events in this population.
Methods
Ethical Approval and Study Design
The study was approved by the ethics committee of the General Hospital of Northern Theater Command and conducted in accordance with the Declaration of Helsinki. The SHIFT-CACS study was a prospective, randomized, open-label, single-center trial conducted from July 2017 to December 2017. Eligible Chinese ACS patients with complicated CAD who had been treated with clopidogrel before coronary angiography and underwent successful drug-eluting stent implantation were included. Complicated CAD was defined based on the Synergy Between PCI With Taxus and Cardiac Surgery score, including left main disease, lesion length >20 mm, tortuous lesions, small vascular lesions, bifurcation lesions, heavy calcification, and in-stent restenosis. Patients with contraindications to ticagrelor or high bleeding risk were excluded.
Randomization and Treatment
After PCI, patients were randomized into three groups: Group A received 90 mg of ticagrelor plus 100 mg of aspirin at 12 hours after the last dose of clopidogrel (T-90 mg-12 h); Group B received 90 mg of ticagrelor plus 100 mg of aspirin at 24 hours after the last dose of clopidogrel (T-90 mg-24 h); and Group C received 180 mg of ticagrelor plus 100 mg of aspirin at 24 hours after the last dose of clopidogrel (T-180 mg-24 h). All patients continued with 90 mg of ticagrelor twice daily plus 100 mg of aspirin once daily for at least 30 days post-discharge.
Platelet Function Assessments
Venous blood samples were collected at baseline (before the first ticagrelor dose), 2 hours, 8 hours, and before discharge. Maximal platelet aggregation (MPA) was measured using light transmittance aggregometry (LTA) with 20 mmol/L adenosine diphosphate (ADP). High on-treatment platelet reactivity (HPR) was defined as MPA >59%.
Outcomes and Follow-Up
The primary endpoint was the comparison of MPA values at 2 hours post-switching among the three groups. Secondary endpoints included MPA values at other time points, HPR rates, and adverse events (bleeding and dyspnea) during hospitalization and at 30-day follow-up. Bleeding events were classified using Bleeding Academic Research Consortium (BARC), Thrombolysis in Myocardial Infarction (TIMI), and PLATO criteria.
Statistical Analysis
The study aimed for a sample size of 36 patients per group, considering a 10% dropout rate. Continuous variables were expressed as mean ± standard deviation (SD) or median, and categorical variables as counts and percentages. Data were analyzed using repeated-measures ANOVA, one-way ANOVA, and linear regression models. A P-value <0.05 was considered statistically significant.
Results
Baseline Characteristics
A total of 102 patients were included, with 98 completing the follow-up. Baseline characteristics were balanced across the groups. The majority were male, with a mean age of 59.06 years. Common comorbidities included hypertension, diabetes mellitus, and dyslipidemia.
Pharmacodynamic Findings
MPA levels were significantly reduced in the T-180 mg-24 h group compared to the T-90 mg-12 h group at 2 hours post-switching (17.23% vs. 28.22%, P=0.017). The T-90 mg-24 h group also showed reduced MPA levels compared to the T-90 mg-12 h group at 8 hours post-switching (18.20% vs. 28.46%, P=0.002). HPR rates did not differ significantly among the groups at any time point.
Safety and Tolerability
Bleeding events classified by BARC, TIMI, or PLATO criteria were similar across the groups. Dyspnea occurred in 28.6% of the T-90 mg-12 h group, 28.6% of the T-90 mg-24 h group, and 25.0% of the T-180 mg-24 h group (P=0.932). Most dyspnea events were mild, with only one patient discontinuing due to intolerability.
Discussion
This study suggests that switching to ticagrelor with a bolus of 180 mg or 90 mg at 24 hours after the last dose of clopidogrel is the optimal strategy for Chinese ACS patients with complicated CAD managed by PCI. The T-180 mg-24 h group showed the greatest reduction in MPA levels, indicating more effective platelet inhibition. The T-90 mg-24 h group also demonstrated significant platelet inhibition, suggesting that a maintenance dose at 24 hours post-clopidogrel is effective. The study also identified a potential negative interaction between clopidogrel and ticagrelor when switching occurs at 12 hours post-clopidogrel, likely due to incomplete clearance of occupied P2Y12 receptors.
The findings align with previous studies showing the benefits of ticagrelor over clopidogrel in reducing ischemic events, particularly in patients with complicated CAD. However, the increased risk of bleeding and dyspnea with ticagrelor necessitates careful consideration of the switching strategy. The study’s results support the updated ESC guidelines recommending a loading dose of ticagrelor in the early phase post-PCI but emphasize the importance of timing to minimize adverse effects.
Limitations
The study was open-label, introducing potential bias, though adjudication of adverse events by blinded clinicians mitigated this. The sample size was relatively small, and larger studies are needed to confirm the findings. Additionally, the study did not evaluate a 180 mg dose at 12 hours post-clopidogrel, which may have provided further insights. Pharmacokinetic measurements of ticagrelor and its metabolites were not performed, limiting the understanding of the underlying mechanisms of the observed interactions.
Conclusion
Switching from clopidogrel to ticagrelor with a bolus of 180 mg or 90 mg at 24 hours after the last dose of clopidogrel is the optimal strategy for Chinese ACS patients with complicated CAD managed by PCI. This approach balances effective platelet inhibition with a manageable risk of adverse events. The study also highlights a potential negative interaction when switching occurs at 12 hours post-clopidogrel, suggesting that 24 hours is the preferable timing for the switch. Further research is warranted to explore the pharmacokinetic mechanisms and confirm these findings in larger populations.
doi.org/10.1097/CM9.0000000000000444
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